Effects of the specific α4ß2 nAChR antagonist, 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine, on nicotine reward-related behaviors in rats and mice.

RATIONALE: Alleviating addiction to tobacco products could prevent millions of deaths. Investigating novel compounds selectively targeting α4ß2 nAChRs hypothesized to have a key role in the rewarding effects of nicotine may be a useful approach for future treatment. OBJECTIVES: The present study was designed to evaluate 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine (4-nitro-PFEB), a potent competitive antagonist of neuronal α4ß2 nAChRs, in several animal models related to nicotine reward: drug discrimination, intracranial self-stimulation (ICSS), conditioned place preference, and limited access to self-administration. METHODS: Long Evans rats were trained in a two-lever discrimination procedure to discriminate 0.4 mg/kg nicotine (s.c.) from saline. Male Sprague-Dawley rats were stereotaxically implanted with electrodes and trained to respond for direct electrical stimulation of the medial forebrain bundle. ICR mice were evaluated using an unbiased place preference paradigm, and finally, male Wistar rats were implanted with intrajugular catheters and tested for nicotine self-administration under limited access (1 h/day). RESULTS: 4-Nitro-PFEB attenuated the discriminative stimulus effects of nicotine, but alone did not produce nicotine-like discriminative stimulus effects. Nicotine-induced facilitation of ICSS reward thresholds was reversed by 4-nitro-PFEB, which alone had no effect on thresholds. 4-Nitro-PFEB also blocked the conditioned place preference produced by nicotine, but alone had no effect on conditioned place preference. Finally, 4-nitro-PFEB dose-dependently decreased nicotine self-administration. CONCLUSIONS: These results support the hypothesis that neuronal α4ß2 nAChRs play a key role in mediating the rewarding effects of nicotine and further suggest that targeting α4ß2 nAChRs may yield a potential candidate for the treatment of nicotine dependence.

Outpatient taxol and carboplatin chemotherapy for suboptimally debulked epithelial carcinoma of the ovary results in improved quality of life: an Eastern Cooperative Oncology Group Phase II Study (E2E93).

PURPOSE: The combination of a platinum compound and paclitaxel is a standard treatment for ovarian cancer. In this cooperative group trial, paclitaxel and carboplatin were combined in an outpatient schedule to determine the clinical benefit, toxicities, and effect on quality of life. PATIENTS AND METHODS: Women with International Federation of Gynecology and Obstetrics stage II to IV epithelial ovarian cancer with suboptimal residual disease (> 1 cm) were eligible. Paclitaxel, 150 mg/m2, was given over 3 hours, followed by carboplatin (area under the curve, 5). This was repeated every 4 weeks for six cycles. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Ovarian Cancer scale. Fifty-nine patients were enrolled, 38 with measurable disease and 21 with evaluable disease. RESULTS: The response rate (complete response + partial response) was 72%. The progression-free interval for patients with measurable disease was 17.5 months and for patients with evaluable disease was 11.1 months. Median survivals were 30.1 months (measurable) and 25.7 months (evaluable). Toxicities were modest. Quality-of-life scores improved significantly during therapy. DISCUSSION: This regimen is ideal for most women with advanced ovarian cancer because it is convenient and well tolerated, with response and survival comparable to those of more aggressive regimens. Overall quality-of-life scores and physical well-being scores improved throughout this outpatient treatment regimen for most patients.

Behavioral effects of flunitrazepam: reinforcing and discriminative stimulus effects in rhesus monkeys and prevention of withdrawal signs in pentobarbital-dependent rats.

Flunitrazepam was evaluated in several procedures that have been used extensively to study the behavioral effects and abuse potential of positive GABA(A) modulators. One group of monkeys (n=3) responded to receive injections of methohexital or saline (i.v.) while other groups (n=2-4/group) discriminated vehicle from either pentobarbital or triazolam. Other monkeys (n=2) received diazepam daily and discriminated flumazenil from vehicle. Finally, the ability of flunitrazepam to prevent the emergence of withdrawal signs in pentobarbital-treated rats was evaluated. Flunitrazepam maintained i.v. self-administration that was, on average, less than that maintained by methohexital and greater than that maintained by saline. In drug discrimination studies, flunitrazepam substituted for pentobarbital and for triazolam and failed to substitute for flumazenil. In rats (n=3-6/group), signs of withdrawal were not evident when flunitrazepam treatment replaced pentobarbital treatment; withdrawal signs emerged when either pentobarbital or flunitrazepam treatment was terminated. Taken together with data from previous studies, these data suggest that the abuse liability of flunitrazepam is comparable to that of other benzodiazepines.

N-Cyclohexylethyl-N-noroxymorphindole: a mu-opioid preferring analogue of naltrindole.

The position of the indole in the indolomorphinans, which includes the delta opioid antagonist naltrindole, is considered to be responsible for the delta opioid selectivity for this class of ligands. Herein is described the N-cyclohexylethyl substituted N-nor-derivative, which is shown to be mu preferring. Thus, the nature of the N-substituent is equally important to the receptor selectivity for this class of ligands.

Dihydroetorphine: physical dependence and stereotypy after continuous infusion in the rat.

In a previous study in this laboratory, exposure of rhesus monkeys to intermittent, high doses of dihydroetorphine for 42 days did not evoke behavioral signs of physical dependence on this opioid either after it was abruptly withdrawn or after challenge with a high dose of naloxone. To investigate further the physical dependence capacity of this opioid, it was given by infusion to rats thereby exposing receptors chronically and continuously to this opioid. Abstinence expressed as body weight loss, irritability, and wet-dog shakes was observed after abrupt withdrawal of the low-dose regimen (5,10, 40 and 40 microg/kg per day for 4 days, respectively). The high-dose regimen (10, 20 and 80 microg/kg per day for 3 days, respectively) produced stereotypy and physical dependence. Although many reported molecular events and dependence studies suggest otherwise, dihydroetorphine's propensity to produce physical dependence, an important determinant of opioid abuse, is real.

Synthesis and in vitro and in vivo activity of (-)-(1R,5R,9R)- and (+)-(1S,5S,9S)-N-alkenyl-, -N-alkynyl-, and -N-cyanoalkyl-5, 9-dimethyl-2'-hydroxy-6,7-benzomorphan homologues.

Two of the synthesized (-)-(1R,5R,9R)-N-homologues (N-but-3-enyl- and N-but-3-ynyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan (9, 13)) were found to be about 20 times more potent than morphine in the mouse tail-flick assay (ED(50) = 0.05 mg/kg), and (-)-(1R,5R, 9R)-N-but-2-ynyl-5,9-dimethyl-2'-hydroxy-6,7-benzomorphan ((-)-(1R, 5R,9R)-N-but-2-ynylnormetazocine, 12) was about as potent as the opioid antagonist N-allylnormetazocine (AD(50) in the tail-flick vs morphine assay = 0.3 mg/kg). All of the homologues examined had higher affinity for the kappa-opioid receptor than the mu-receptor except (-)-N-but-2-ynyl-normetazocine (12), which had a kappa/mu ratio = 7.8 and a delta/mu ratio = 118. The (-)-N-2-cyanoethyl (3), -allyl (8), and -but-3-ynyl (13) analogues had good affinity (<10 nM) for delta-opioid receptors. Two homologues in the (+)-(1S,5S,9S)-normetazocine series, N-pent-4-enyl (24) and N-hex-5-enyl (25), were high-affinity and selective sigma(1)-ligands (K(i) = 2 nM, sigma(2)/sigma(1) = 1250, and 1 nM, sigma(2)/sigma(1) = 750, respectively); in contrast, N-allylnormetazocine (22) had relatively poor affinity at sigma(1), and its sigma(1)/sigma(2) ratio was <100.

Paclitaxel, carboplatin, and hexamethyl-melamine (taxchex) as first-line therapy for ovarian cancer.

BACKGROUND: The addition of hexamethylmelamine to therapy with cisplatin, cyclophosphamide, and doxorubicin significantly enhanced outcomes of patients with advanced ovarian cancer. Hexamethylmelamine, also known as altretamine, has potent antineoplastic activity when used as a single agent in patients who have failed to respond to both platinum-based and paclitaxel therapy. We have conducted a pilot study to evaluate the efficacy and safety of adding this drug to the popular ovarian cancer regimen of paclitaxel plus carboplatin. METHODS: Patients with advanced ovarian, fallopian tube, or primary peritoneal cancer (International Federation of Gynecology and Obstetrics stages IIA, IIIC, and IV) were prospectively enrolled to receive six cycles, repeated every 4 weeks, of paclitaxel (150 mg/m2 i.v., day 1), carboplatin (AUC 5.0 i.v., day 1), and hexamethylmelamine (150 mg/m2 p.o., days 2-15). Colony stimulating factors were prohibited. Response and toxicity were monitored by use of Eastern Cooperative Oncology Group criteria. RESULTS: Twenty patients were enrolled, 18 with ovarian cancer, one with fallopian tube cancer, and one with peritoneal cancer; 17 of these patients were evaluable for response and toxicity. At a median follow-up of 6.5 months, 13 of the patients had a complete response (76%), and four had progressive disease. Three of those with a complete response had a recurrence within 1 year of completing treatment. Toxicity was acceptable, with myelosuppression the most severe adverse effect; one patient had grade 3 anemia, one patient had grade 4 thrombocytopenia, and 12 patients had grade 4 neutropenia. Quality of life showed improvement over the course of therapy, particularly in the physical well-being subscale. CONCLUSION: The addition of hexamethylmelamine to paclitaxel and carboplatin is a well-tolerated multidrug combination for women with advanced ovarian cancer that deserves further testing in a phase III study.

Stereoselective mu- and delta-opioid receptor-related antinociception and binding with (+)-thebaine.

In vivo and in vitro binding studies with natural thebaine and its enantiomer, (+)-thebaine were conducted to elucidate further their interactions with the opioid system. (-)-Thebaine a key intermediate in the biosynthesis of morphine in the poppy plant (Papaver somniferum) and in mammalian tissue, was poorly effective antinociceptively in mice at doses to 30 mg/kg. Its principal behavioral manifestation was lethal convulsions. Naltrindole, at doses of 1 and 10 mg/kg did not block either the convulsions or lethal effects, suggesting that the delta-opioid receptor system was not involved in this action. Surprisingly, the dextrorotatory isomer exhibited significant antinociceptive activity in the tail-flick [ED50 = 8.9 (3.4-22.1) mg/kg], hot-plate [ED50 = 22.9 (10.9-48.1) mg/kg] and phenylquinone [ED50) = 1.9 (1.6-9.5) mg/kg] assays. Studies with opioid receptor-subtype antagonists, beta-funaltrexamine, nor-binaltorphimine and naltrindole, indicated that antinociception was associated with mu- and delta-opioid receptors. Results of displacement experiments supported the in vivo data. Significant competition for [3H]diprenorphine binding with both isomers for cloned mu- and delta-opioid receptors was observed. However, (-)-thebaine was more effective at the delta-opioid receptor (Ki = 1.02+/-0.01 microM) whereas (+)-thebaine was more effective at the mu-opioid receptor ( Ki = 2.75+/-0.01 microM). Opioid-induced antinociception associated with unnatural thebaine raises the possibility of additional mu- and delta-opioid receptor sites.

Anti-allodynic actions of intravenous opioids in the nerve injured rat: potential utility of heroin and dihydroetorphine against neuropathic pain.

Neuropathic pain has been suggested to be resistant to treatment with opiates. Such perceived lack of opioid responsiveness may be due to the dose-range over which specific opioid compounds have been studied as well as the efficacy of these compounds. Dihydroetorphine is a novel opiate that demonstrates significantly greater analgesic potency compared to morphine, and which also demonstrates diminished capacity for producing physical dependence in laboratory animals. The present study compared the intravenous (i.v.) efficacy, potency and duration of action of dihydroetorphine, fentanyl, heroin and morphine in producing anti-allodynic actions in a rat model of neuropathic pain (ligation of the L5/L6 nerve roots). All compounds produced significant anti-allodynic activity with dihydroetorphine being the most potent (A50 of 0.2 microg kg(-1), i.v.). Morphine was approximately 7440 times less potent than dihydroetorphine while heroin and fentanyl were approximately 163.5 and 6.9 times less potent in producing anti-allodynic actions. Dihydroetorphine also showed a maximal effect at 0.6 microg kg(-1) in all animals tested, while 100 microg kg(-1) was required for heroin to produce a maximal effect. Fentanyl and morphine did not elicit a maximum anti-allodynic response (74 and 76% maximum possible effect (%MPE), respectively). As expected, fentanyl showed a relatively brief duration of action (approximately 20 min at the highest tested dose), while dihydroetorphine and morphine demonstrated anti-allodynic actions for up to 45 min. Heroin had the longest duration of action, producing significant anti-allodynic effects for up to 90 min. These data show that dihydroetorphine and heroin produce potent and long-lasting anti-allodynic actions in this model. Additionally, in contrast to morphine and fentanyl, both dihydroetorphine and heroin were able to achieve a maximal response. The remarkable potency, maximal efficacy and duration of action of these compounds, particularly dihydroetorphine, suggests that these compounds may warrant further examination as potential therapeutic treatments for neuropathic pain states.

3-Alkyl ethers of clocinnamox: delayed long-term mu-antagonists with variable mu efficacy.

In recent years there has been considerable interest in the relationship between clocinnamox (C-CAM) and its methyl ether methoclocinnamox (MC-CAM). While C-CAM appears to be an insurmountable mu-antagonist, MC-CAM has been shown to be a potent partial agonist at mu-opioid receptors. To further investigate this relationship we prepared other ethers of C-CAM and evaluated these in opioid receptor binding assays and in vivo in mouse antinociceptive assays and in morphine-dependent monkeys. In opioid binding assays, the ethers were generally mu-selective with affinity equivalent to that of C-CAM itself. Although they displayed little or no efficacy in vitro, some of the ethers showed substantial agonist activity in the in vivo antinociceptive tests. Two of the ethers, the propargyl ether 7 and the cyclopropylmethyl ether 5, were chosen for more detailed analysis in vivo. 7 was shown to have significant mu-agonist character and was able to substitute for morphine in morphine-dependent monkeys. Interestingly, when this agonist effect abated, 7 displayed long-lasting mu-antagonism. In contrast, 5 displayed little agonist activity in vivo and was characterized as a potent, long-acting mu antagonist. Although further work is needed to determine whether metabolism is a crucial factor in determining the pharmacological profile of these ethers, it is clear that 3-O-alkylation is a useful means of varying the mu efficacy displayed by this class of acyl-substituted 14-aminomorphinones. MC-CAM itself has generated considerable interest as a potential pharmacotherapy for opiate abuse. These analogues with differing mu efficacy but retaining the long-lasting mu-antagonist effects provide further opportunities for the development of treatment drugs.

Radiologic placement of long-term subcutaneous venous access ports in children.

OBJECTIVE: The purpose of this study was to review the results of radiologically placed subcutaneous venous access ports in a pediatric population requiring long-term venous access. CONCLUSION: Sixteen of 20 patients had no significant problems with their ports. In the pediatric population, radiologically placed subcutaneous venous access ports offer a high success rate, a low complication rate, and significant cost savings over surgically placed ports.

A killing of Baby Doe.

An anencephalic infant died in the Neonatal Intensive Care unit six hours after birth. Eighteen months later, in a discussion of intrusive federal "Baby Doe" regulations with co-workers at the hospital, a registered nurse mentioned that he had found a way to avoid these provisions, and that he had in fact done so on one occasion by killing this particular infant. A co-worker related his story to police, and the "wheels of justice" were set into motion. I describe the chronology of events and the pathologic findings in this case of infanticide, purportedly committed "with mercyaforethought."

Evaluation of the discriminative stimulus and reinforcing effects of dihydroetorphine.

These experiments examined whether dihydroetorphine (DHE) could serve as a reinforcer in rhesus monkeys and evoke the discriminative stimulus effects of heroin (HER) in rats, two procedures useful in predicting the overall abuse potential of compounds. Rhesus monkeys were trained to self-administer i.v. HER (10 micrograms/kg for monkeys M-BA, M-NI, and M-HO; 3 micrograms/kg for monkey M-PO) during daily; 2-h experimental sessions under FR 10 Timeout 4 min schedules. VEH and doses of HER (1-30 micrograms/kg), codeine (COD; 30-1000 micrograms/kg), and DHE (1-100 ng/kg) were then substituted for the HER maintenance doses. Results indicated that DHE served as a reinforcer. The dose of DHE that maintained peak numbers of infusions was 171 and 8571 times smaller than those maintaining peak numbers of infusions of heroin and codeine, respectively. Additionally, male Sprague-Dawley rats were trained to discriminate 0.3 mg/kg HER s.c. from vehicle (VEH) in an FR 10 (fixed-ratio 10), food-reinforced, operant procedure. During tests, HER, morphine (MOR), and DHE dose-dependently evoked heroin-lever responding with ED50s of 0.055, 0.74, and 0.00033 mg/kg, respectively. These results indicate that DHE is self-administered by rhesus monkeys, and potently produces the discriminative stimulus effects of HER in rats, and suggest that DHE would have a substantial potential for abuse.

Peripherally inserted central catheters: experience in 523 children.

PURPOSE: To evaluate prospectively the use of peripherally inserted central catheters in a large pediatric population. MATERIALS AND METHODS: During a 3-year period, data were collected prospectively on 523 consecutive attempts to place peripherally inserted central catheters in children. Patients underwent radiologically guided placement because attempts were unsuccessful on the inpatient units or a patient request was made. Fluoroscopy with use of contrast material and venography were used to place catheters and document the position of the catheter tip. Follow-up data were collected until treatment cessation or catheter removal. RESULTS: Among 523 attempts, 486 (92.9%) catheters were successfully placed. In the 37 (7.1%) unsuccessful cases, more than half of these children were younger than 24 months of age or weighed less than 5 kg. Ages of patients in whom 523 placement attempts were made ranged from 3 weeks to 18 years (mean, 6.9 years). Catheters were in place from 1 to 390 days (mean, 20 days). Frequency of infection was 1.9% (nine cases); incidence of infection was 0.93 per 1,000 catheter-placement days. There were two cases (0.4%) of central venous thrombosis. Most patients were discharged within 2 days of catheter placement. CONCLUSION: Fluoroscopically guided placement of peripherally inserted central catheters is a safe and effective method for establishing intermediate- and long-term central venous access in the pediatric population.

Potent reinforcing effects of dihydroetorphine in rats.

Dihydroetorphine is a novel opioid that is an extremely potent analgesic in rodents. The reinforcing potency was determined in rats trained to self-administer heroin and compared to those of fentanyl, heroin, 6-acetylmorphine and morphine for assessment of the abuse potential of dihydroetorphine using a procedure that determines the dose-effect curve in individual sessions. Dihydroetorphine produced a bimodal dose-effect curve similar to that of other opioids. Potency ratios were determined with morphine for the ascending and descending limbs of the dose-effect curve, as well as the dose that yielded maximal response rate. Fentanyl, heroin and 6-acetylmorphine were approximately 100, 8 and 2 times more potent than morphine in maintaining self-administration, respectively. Dihydroetorphine was roughly 1500 to 3000 times more potent than morphine, however, depending upon the limb of the dose-effect curve used for comparison. These potency ratios of dihydroetorphine to morphine were somewhat less than has been reported for analgesia assays, and therefore this compound may have some clinical advantages over other opioids. However, these studies indicate significant abuse liability for dihydroetorphine given its potency in maintaining self-administration in these animals.

Etorphines: mu-opioid receptor-selective antinociception and low physical dependence capacity.

Comparative analgesic studies revealed that dihydroetorphine was more potent than etorphine in the tail-flick and hot-plate tests, respectively and nearly equipotent in the phenylquinone assay. Both compounds were short acting. Studies with selective opioid receptor antagonists beta-funaltrexamine, nor-binaltorphimine and naltrindole revealed that both etorphines were mu-selective agonists. Presumptive evidence for competitive antagonism of these compounds with naloxone was provided by Schild regressions with slopes of near unity. In a suppression test in rhesus monkeys maximally dependent on morphine, dihydroetorphine and etorphine dose-dependently replaced morphine. Drug-naive simians chronically exposed to frequent, intermittent and escalating doses of dihydroetorphine for 42 days showed few withdrawal signs when challenged with large doses of naloxone or were abruptly withdrawn from this drug. The results suggest that these atypical opioids may be useful in the clinical treatment of pain and opiate drug abuse.